New research into the derivation and expansion of cell lines suitable for human administration promises to usher in a brave new world medical care. Devastating and previously intractable disease conditions may yield to the promise of regenerative medicine, providing that science continues to benefit from important new discoveries in the cell biology of neurons and neural precursor cells.
Amongst the disease conditions in need of a clinical advance are those relating to neurological dysfunction. Near the top of the list is Parkinson's disease, an idiopathic, slowly progressive, degenerative disorder of the central nervous system, characterized by slow and decreased movement, muscular rigidity, resting tremor, and postural instability. The symptoms ensue from progressive deterioration of pigmented neurons in the substantia nigra, locus caeruleus, and other brain stem dopaminergic cells, causing a depletion of the neurotransmitter dopamine. Parkinson's disease is the fourth most common neurodegenerative disease of the elderly, affecting 0.4% of those over 40, and 1% of those over 65. Regardless of the age of presentation, the disease often has devastating consequences for those afflicted.
What makes afflictions of the nervous system so difficult to manage is the irreversibility of the damage often sustained. A central hope for these conditions is to develop cell populations that can reconstitute the neural network, and bring the functions of the nervous system back in line. Anecdotal evidence shows that transplantation of fetal dopaminergic neurons may reverse the chemical abnormality in Parkinson's disease. But there is a severe shortage of suitable tissue.
For this reason, there is a great deal of evolving interest in neural progenitor cells. Various types of lineage-restricted precursor cells renew themselves and reside in selected sites of the central nervous system (Kalyani et al., Biochem. Cell Biol. 6:1051, 1998). Putative neural restricted precursors (Mayer-Proschel et al., Neuron 19:773, 1997) cells express a polysialylated isoform of the neural cell adhesion molecule (PS-NCAM). They reportedly have the capacity to generate various types of neurons, but not glial cells. On the other hand, putative glial restricted precursors (Rao et al., Dev. Biol. 188: 48, 1997) apparently have the capacity to form glial cells but not neurons. Putative neural precursors from fetal or adult tissue are further illustrated in U.S. Pat. Nos. 5,852,832; 5,654,183; 5,849,553; and 5,968,829; and WO 09/50526 and WO 99/01159.
Unfortunately, it has not been shown that progenitors isolated from neural tissue have sufficient replicative capacity to produce the number of cells necessary for human clinical therapy.
An alternative source is pluripotent cells isolated from early embryonic tissue. Embryonic stem (ES) cells were first isolated from mouse embryos over 25 years ago (G. R. Martin, Proc. Natl. Acad. Sci. U.S.A. 78:7634, 1981). ES cells are believed to be capable of giving rise to progeny of virtually any tissue type of the same species. Li, Smith et al. (Cur. Biol. 8:971, 1998) report generation of neuronal precursors from mouse ES cells by lineage selection. Bjorklund et al. reported the production of functional dopaminergic neurons from mouse ES cells (Proc. Natl. Acad. Sci. USA 19:2344, 2002).
Human ES cells were isolated much more recently (Thomson et al., Science 282:114,1998). Human ES cells require very different conditions to keep them in an undifferentiated state, or direct them along particular differentiation pathways (U.S. Pat. Nos. 6,090,622 & 6,200,806; Australian Patent AU 729377, and PCT publication WO 01/51616). For this reason, much less is known about how to prepare relatively homogeneous cell populations from human ES cells.
There is a pressing need for technology to generate more homogeneous differentiated cell populations from pluripotent cells of human origin.